GABA-A receptors and Addiction - recommended reading (references) Flashcards
GABA-A Receptor; Positive and Negative Allosteric Modulators
Author
Olsen
GABA-A Receptor; Positive and Negative Allosteric Modulators
Abstract
GABARs are members of the ligand-gated ion channel receptor superfamily, a chloride channel family
The subtypes present on GABARs demonstrate different brain regional and subcellular localization, age-dependent expression and potential for plastic changes with experience including drug exposure
GABARs are targets of agonist depressants and antagonist anticonvulsants, but most GABAR drugs act at an allosteric site
GA including alcohols and neurosteroids act at GABAR subunit-interface trans-membrane sites
Ethanol at high anaesthetic doses and low intoxication doses acts on GABAR subtype dependent transmembrane domain s
GABA-A Receptor; Positive and Negative Allosteric Modulators
GABAA vs GABAB
Bicuculline is a specific GABAA antagonist
Baclofen is a specific GABAB agonist
Both types of GABA receptor participate in both postsynaptic inhibition and presynaptic inhibition. Both forms of GABA receptors exist at both synaptic and extrasynaptic locations
GABAArs demonstrate considerable extrasynaptic localization where they function to mediate the tonic inhibitory currents, separate from the phasic synaptic transmission
Extrasynaptic; alpha4, 5, 6
Synaptic; alpha 1,2,3
GABAA; pentameric ligand gated chloride channel - activation leads to influx of chloride. Sedation, anxiolysis, anticonvulsant and muscle relaxation
GABAB; heterodimeric Gi/o protein-coupled receptors which activate K+ channels and inhibit Ca2+ channels. Muscle spasticity (baclofen is GABAB agonist)
GABA-A Receptor; Positive and Negative Allosteric Modulators
Describe the GABAAR in terms of ligand sites
3 major drug sites; GABA sit (agonist/ antagonist) in extracellular domain
Picrotoxin site (channel blocker; NAM) in the transmembrane domain
BZD site (PAM) in the extracellular domain
High affinity ethanol site is located at extrasynaptic delta subunit GABAARs; modified BZD binding site which in turn is a modified GABA binding site
GABA-A Receptor; Positive and Negative Allosteric Modulators
Describe BZs
Studies have demonstrated BZ drugs to act as CNS depressants and act as PAMs on GABAARs
BZ receptor binding is enhanced by GABA in the test tube
Alpha 4 and 6 GABAAR subtypes partner with delta subunits producing extrasynaptic GABAARs that mediate tonic inhibitory currents in the major cell populations including cerebellar and hippocampal granule cells = not BZD sensitive
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe the role of alpha 1 beta gamma 2 receptors
Sedation Addiction Anterograde amnesia Anticonvulsant activity Premature cortical plasticity
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe the role of alpha 2 beta gamma 2 receptors
Anxiolysis Anti- hyperalgesia Antidepressant Cognition in SZ Myorelaxation
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe the role of alpha 3 beta gamma 2
Sensorimotor gating
Decrease in thalamic oscillations
Myorelaxation
Antihyperalgesia
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe the role of alpha 5 beta gamma 2
Sensorimotor gating
Cognitive impairment
Myorelaxation
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Abstract
GABAA receptors are a family of ligand gated ion channels which are essential for the regulation of the CNS function
BZD’s target GABAA receptors containing the alpha 1, 2, 3 or 5 subunits non-selectively - most widely prescribed drug for insomnia and anxiety disorders
Identification of key functions related to specific subunits of BZDs suggests that selective compounds could overcome the limitations of classical BZDs and may be valuable for indications such as analgesia, depression, SZ, cognitive enhancement and stroke
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
How do BZDs mediate their action?
Via modulatory binding site (BZD site)
on GABAA receptors
In contrast to barbiturates, the BZD binding effect is self limiting; the conductance of the channel in the presence of GABA and BZD is not higher than the conductance that can be achieved with high conc of GABA alone.
Additionally, in contrast to barbiturates, BZDs do not open the chloride channel in the absence of GABA
GABA induced chloride influx hyperpolarizes the post-synaptic neuron
Many GABAA receptors contain two alpha subunits, two beta subunits and one gamma with 2 GABA binding sites formed by alpha and beta subunits
The binding site for BZD is formed by the alpha and gamma subunit
GABAA receptors containing alpha 4 or 6 = BZD insensitive
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe the role of GABAA receptor in pharmacological terms
BZD
Hypnotic drugs; zopiclone
Barbiturates
GA; etomidate and Propofol
Beta 3 k/o mice are unable to be immobilized by etomidate or Propofol, suggesting the role of beta 3 in immobilization
Volatile anaesthetics such as isoflurane, enflurane and sevoflurane act at a variety of targets, GABAA one of which
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe GABAAR mediated events on the post-synaptic membrane
Increase in postsynaptic membrane conductance (shunting inhibition)
A change in the membrane potential due to movement of chloride ions through the membrane (hyperpolarizing inhibition)
Synaptic receptors that detect millimolar concentrations of GABA mediate fast inhibitory post synaptic potentials (IPSPs) whilst extrasynaptic receptors which detect micromolar concentrations of GABA mediate slower IPSPs alongside tonic conductance
Tonic and phasic conductance’s underlie different physiological and behavioural processes
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe the role of human mutations in GABAAR subunits
Point mutations in alpha 1 and gamma 2; genetic epilepsy
SNPs in gene encoding alpha 2; alcohol dependence, illicit drug dependence
Beta 1 subunit of GABAAR has been linked to alcohol dependence and BAD
Genes encoding alpha 1, 6 beta 2 and pi subunits have been linked to SZ
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
How is the function of individual subunits of GABAAR identified?
Genetically modified mice in which GABAAR alpha subunits are rendered insensitive to diazepam via histidine to arginine point mutation - abolish binding of diazepam whilst conserving GABA nT action
Alpha 1 (H101R) mice: sedative, anticonvulsant action and amnesic action were reduced however anxiolytic action still present
Alpha 2 (H101R); anxiolytic like action and myorelaxant action missing whilst sedative action preserved
Tolerance = alpha 5 Addictive = alpha 1
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe binding and functional selectivity
Ligands at BZD site of GABAAR are allosteric modulators; e.g. they modify the efficacy and/or affinity of agonists e.g. GABA and thus regulate their activity
They can either by PAMs or NAMs depending on the stabilization of different confirmations of the receptor
Prototypic ligands for PAM, NAM and BZ site antagonist;
PAM = diazepam
NAM = beta-CCM
BZ site antagonist = flumazenil
Selectivity of a ligand for a specific GABAA receptor subtype can be obtained by binding i.e. by forming a receptor-ligand complex, or efficacy by eliciting a biological response after binding to the receptor
Binding and efficacy determine a potency profile
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe the role of the GABAA site in addiction
All addictive drugs act to increase dopamine levels within the mesolimbic dopamine system
BZDs increase the firing of f DA neurons within the VTA by decreasing the activity of GABAergic interneurons
DA neurons in VTA express alpha 3 GABAARs; in contrast; GABAergic interneurons in the VTA express alpha 1 containing GABAA receptors which results in the disinhibition of DA neurons
Unselective BZDs modulate alpha 3 GABAARs on DA neurons within the VTA, but the disinhibition via alpha 1 containing GABAARs on interneurons is the predominant effect
This disinhibition triggers drug-evoked synaptic plasticity in excitatory glutamergic afferents onto DA neurons in the VTA and underlies drug reinforcements. In mice, a single dose of BZDs has been shown to elicit such neuroplastic changes
Alpha 1(H101R) mice showed no preference for midazolam indicating that alpha 1 containing GABAA receptors are essential for midazolam self-administration
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe the role of BZDs in analgesia
Intrathecal BZDs act on central GABAARs such as those in the PAG - an area involved with the regulation of descending antinociceptive tracts; are pro-nociceptive at supraspinal sites.
In contrast, GABAARs in the spinal cord have anti-hyperalgesic actions
Alpha 2(H101R) and alpha 3(H101R) mice; intrathecal diazepam has a significantly reduced in models of inflammatory pain and neuropathic pain = spinal alpha 2 and alpha 3 containing GABARs mediate anti-hyperalgesic actions of intrathecal diazepam
Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes
Describe the role of BZDs on SZ
Alpha 3 knockout mice and alpha 5 partial k/o mice display deficits in sensorimotor fating, as determined by prepulse inhibition of acoustic startle, supporting a potential involvement of alpha 3 and alpha 5 containing GABAA receptors
Recent evidence suggests a role of alpha2/3 PAMs on cognitive impairment in SZ
In the cortex and hippocampus, hypofunction of NMDA receptors on GABAergic interneurons, which form synapses with the axon initial segment (AIS) of cortical pyramidal neurons to result in decreased inhibition of glutamergic pyramidal neurons. PM SZ brains show an upregulation of alpha 2 subunit in the AIS; compensatory adaptation
